Oxalic acid salts of n-dialkylamino-ethyl-alpha-(naphthyl - 1) delta-pent-4-enoic acid

ABSTRACT

ACID SALTS OF ESTERS OF A-(1-NAPHTHYL)-DELTA-PENT-4-ENOIC ACID ARE OBTAINED BY THE REACTION OF THE ACID WITH AN AMINO DERIVATIVE OF THE FORMULA   Y-(CH2)2-N(-R2)-R3   WHEREIN R2 AND R3 ARE LOWER ALKYL RADICALS AND Y IS SELECTED FROM THE GROUP CONSISTING OF THE HALOGENS AND THE HYDROXY RADICAL TO OBTAIN ESTERS OF THE FORMULA   NAPHTH-1-YL-CH(-CH2-CH=CH2)-COO-(CH2)2-N(-R2)-R3   WHICH CAN BE CONVERTED TO THE ACID SALTS.

United States Patent Int. Cl. C07c 69/76 US. Cl. 260-469 3 Claims ABSTRACT OF THE DISCLOSURE Acid salts of esters of 0c( l-naphthyl)-delta-pent-4-enoic acid are obtained by the reaction of the acid with an amino derivative of the formula /R2 Y( 0 H2) 2-N wherein R and R are lower alkyl radicals and Y is selected from the group consisting of the halogens and the hydroxy radical to obtain esters of the formula R2 CHOOO(OH2)zN OHCH=CH2 Ra which can then be converted to the acid salts.

This application is a divisional application of application Ser. No. 352,963 filed Mar. 18, 1964, now US. Patent No. 3,334,096.

The present invention relates to new nitrogenous bases substituted by at least one naphthyl or naphthyl-methyl radical, and particularly to a new series of amino esters and their acid salts which are thus substituted.

The N-diethylamino ethyl beta-(l-naphthyl)-beta'-tetrahydrofuryl isobutyrate, endowed with antispasmodic properties has formed the subject of the US. patent application No. 308,662 of Sept. 13, 1963, now abandoned.

Certain new amino esters and their acid salts, endowed with very interesting antispasmodic properties, have been discovered according to the invention. These compounds are the members of the class which consists in their free bases, their acid salts and their quaternary ammonium derivatives, of the compounds represented by the general formula:

in which R and R are lower alkyl radicals.

The new compounds can be obtained according to the invention by condensation of an acid of the formula OH2=CH Hg with an amino derivative of the formula R2 Y-(CHz)zN 3,567,761 Patented Mar. 2, 1971 in which Y is a member of the group consisting of the halogens and the hydroxy radical, and R and R have the same meanings as above.

It is possible to prepare the new amino esters according to a preferred modification of the invention by azeotropic esterification, consisting in heating together under reflux the acid and the hydroxyl derivative in the presence of an entraining agent for the water of esterification.

The acids used as initial products in the preparation of the above amino esters are described in US. patent application Ser. No. 174,684 filed Feb. 21, 1962, now US. Patent No. 3,257,420.

The mineral and organic acid salts of the new compounds according to the invention, such as the salts of phosphoric, oxalic and fumaric acids, are obtained by neutralisation, and the quaternary ammonium derivatives by reaction of an alkyl halide, particularly methyl iodide, with the corresponding amino esters, which thus constitute intermediate derivatives in the preparation of their derivatives.

Used in the Magnus test on the isolated intestine of a guinea pig, the new compounds according to the invention have an antispasmodic activity which is 10 to 40 times better than that of papaverine.

In the form of an addition salt, these compounds have a peripheral and coronary vasodilatory action which is comparable in very advantageous manner to that of the best products so far employed in this indication.

On the other hand, it is to be observed that the local anaesthetic activity of these derivatives is likewise very high, and this may reach 5 to 10 times that of diethylaminodimethyl-2,6-acetanilide hydrochloride.

The processes for the preparation and the physical constants of various compounds which form the subject of the present invention are hereinafter described as non-limitative examples.

EMMPLE 1 Acid oxalate of N-dimethylaminoethyl alphal-naphthyl) -delta-pent-4-enoate C zr zaN O a 7 g. (0.0227 mol) of dimethylaminoethyl alpha-(lnaphthyl)-delta-pent-4-enoate, obtained for example by azeotropic esterification in toluene of alpha-( 1-naphthyl)- delta-pent-4-enoic acid, are dissolved in 8 cc. of acetone and are caused to react with a solution of 2.97 g. (0.02. mol) of dihydrated oxalic acid in 8 cc. of acetone. As soon as the addition of the oxalic acid is completed, the expected salt precipitates.

7.6 g. of white solid are obtained, the yield being (theoretical quantity=9.5 g.).

After having been recrystallised twice from a mixture of ethyl acetate and alcohol, the product is analytically pure and has the following constants:

Melting point-M.P.=l64-165 C. (capillary tube),

l57159 C. (with capillarly tube in a Gallenkamp apparatus) acidity index: calculated=289; found 286 Gravimetric analysis.-Calculated (percent): C, 65.10; H, 6.50; N, 3.61. Found (percent): C, 65.02; H, 6.62; N, 3.64.

3 EXAMPLE 2 Acid oxalate of N-diethylaminoethyl alpha- (l-naphthyl) -delta-pent-4-enoate 5 g. (0.0152 moi) of N-diethylaminoethyl alpha-( 1- naphthyl)-delta-pent-4-enoate, obtained for example by the action of belta-ch10roethyl-N-diethylamine on alpha- (l-naphthyl)-delta-pent-4-en0ic acid, are caused to react with 2 g. (0.0152 m01:l.93 g.) of dihydrated oxalic acid, under the conditions of Example 1.

5.5 g. of crystals are obtained with a melting point of l081l0 C. (capillary tube).

After being recrystallised three times from a mixture of ethyl acetate and alcohol, the product is analytically pure and has the following constants:

M.P.=122124 C. (capillary tube) acidity index: calculated=269; found=265 Gravimetrz'c analysis.Calculated (percent): C, 66.51; H, 7.63; N, 3.37. Found (percent): C, 65.92; H, 6.90; N, 3.36.

The compounds in accordance with the present investigation were tested to determine their antispasmodic and peripheral and coronary vasodilatory activity.

The antispasmodic activity of these compounds has been studied on the isolated intestine, and the spasms caused by barium chloride, to determine the papverinic activity of the product, as related to that of papverine, capable of arresting or increasing the movements induced in the isolated duodenum of a rat or the intestine of a guinea pig. The vasodilatory activity was determined by means of several methods, especially by means of the Langendortf apparatus which enables the coronary output of an isolated heart to be measured, e.g., that of a rabbit. The Langendorff coefiicient represents the minimum dosage of the product causing the same output as 10* grams of papaverine, which is given the coefficient 100. The vasodilatory activity is also expressed by the femoral rotametric coefficient; and this coeificient is determined as above by measuring the blood output into the femoral artery of a dog; and in this case, the products were applied by intravenous injection, or by intra-arterial Isolated intestine spasms Femoral Langenby BaClz rotamentry dorft Oxalate acid of (naphthyl-l)pentenedelta-4-oate of N-diethylaminoethyL 200 87 37 Oxalate acid of (naphthyl-l)pentene delta--oate of N-dimethylan1i110- ethyl 330 270 66 It will be obvious to those skilled in the art that various changes may be made without departing from the scope of the invention and the invention is not to be considered limited to what is described in the specification.

What is claimed is:

1. An acid oxalate of a compound of the formula:

CHz-CH CH wherein R and R are lower alkyl radicals.

2. The acid oxalate of N-dimethylaminoethyl-u-(lnaphthyl)-delta-pent-4-enoate according to claim 1.

3. The acid oxalate of N-diethylaminoethyl-a-(l-naphthyl)-delta-pent-4en0ate according to claim 1.

References Cited UNITED STATES PATENTS 3,257,420 6/1966 Szarvesi et a1 260347.4

FOREIGN PATENTS 1,289,597 3/1963 France.

CHARLES B. PARKER, Primary Examiner E. J. GLEIMAN, Assistant Examiner US. Cl. X.R.

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No. 567 761 Dated March 2. 1971 Inventor(s) Etienne SZARVASI at 8.1.

It is certified that error appears in the above-identified paten and that said Letters Patent are hereby corrected as shown below:

001. 2, the formula at line as,

should be Signed and sealed this 6th day of July 1971 (SEAL) Attest:

EDWARD M.FI.ETCHER,JR. WILLIAM E. SGHUY Attesting Officer Commissioner of 

